The protection and deprotection of carboxyl esters is an important part of many syntheses wherein carboxylate groups are involved. For instance, this protection and deprotection does often play a role in the synthesis of semi-synthetic cephalosporins (SSC's) and semi-synthetic penicillins (SSP's). SSC's are derivatized congeners of 7-aminocephalosporanic acid (7-ACA) or 7-aminodesacetoxycephalosporanic acid (7-ADCA) and salts and esters thereof; SSP's are derivatized congeners of 6-aminopenicillanic acid (6-APA).
In synthetic schemes leading to SSC's and SSP's a variety of protecting groups is often employed. An important feature in protecting group strategy usually is blocking and deblocking of the carboxyl function since said carboxyl functions can undergo decarboxylation if left unreacted (J. Amer. Chem. Soc. 1969, 91, 1401). Protection is achieved using esterification with an alcohol that can be removed under acidic or neutral conditions. Important industrial examples of 4-carboxyl protecting groups are allyl, benzhydryl, benzyl, tert-butyl, 4-methoxybenzyl, 4-nitrobenzyl and trichloroethyl. The known methods for removal of protecting groups are either expensive (trifluoroacetic acid), difficult to process because of complexation (zinc/acetic acid), or suffer from low yields (hydrogenolysis in case of benzhydryl and benzyl).
It is accordingly an object of the present invention to provide a new and improved process for converting carboxyl esters to the corresponding acid in high yield without the production of unwanted by-products.
It is also an object of the invention to provide new compounds by the application of this process, as for instance (6R,7R)-3-(2,4-dinitrostyryl)-7-phenylacetamido-ceph-3-em-4-carboxylic acid (cefesone), and the conversion in salts and esters thereof, and the E-isomers of the same. The chemical name of the racemic mixture has recently been indicated in J. Clin. Micr. 1995, 1665, but a process to prepare the same has not been published up to now.
Aluminum trichloride-promoted hydrolysis of cephalosporin esters is a procedure reported for the hydrolysis of benzyl esters (Tetrahedron Lett. 1979, 2793), benzhydryl esters (Pure & Appl. Chem. 1987, 59, 1041), and 4-methoxybenzyl esters (Pure & Appl. Chem. 1989, 61, 325).
Surprisingly, it has been found that other Lewis acids, like tellurium tetrachloride, tin tetrachloride or titanium tetrachloride, can be applied for the high yield hydrolysis of carboxyl esters, such as tert-butyl and 4-methoxybenzyl.